rs121907913
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001368894.2(PAX6):c.76C>T(p.Arg26Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001368894.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAX6 | NM_001368894.2 | c.76C>T | p.Arg26Trp | missense_variant | 5/14 | ENST00000640368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX6 | ENST00000640368.2 | c.76C>T | p.Arg26Trp | missense_variant | 5/14 | 5 | NM_001368894.2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Aniridia 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Wessex Regional Genetics Laboratory, Salisbury District Hospital | Aug 15, 2019 | - - |
Irido-corneo-trabecular dysgenesis Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Molecular Medicine, University of Pavia | Jul 28, 2023 | - - |
Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 31, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg26 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been observed in individuals with PAX6-related conditions (PMID: 18483559, 31700164, 34101622), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAX6 protein function. ClinVar contains an entry for this variant (Variation ID: 800389). This missense change has been observed in individual(s) with clinical features of aniridia (PMID: 27878435, 32360764). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 26 of the PAX6 protein (p.Arg26Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at